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Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1 , Abcg5 , and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1 , Abca1 , Abcg5 , and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% ( P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRα-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRα independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat. cholesterol absorption; ABC transporters; Npc1l1; fatty acids Address for reprint requests and other correspondence: N. de Wit, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen Univ., Bomenweg 2, NL-6703 HD, Wageningen, the Netherlands (e-mail: nicole.dewit@wur.nl )
AJP - Gastrointestinal and Liver Physiology – The American Physiological Society
Published: May 1, 2008
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